Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Translational Therapeutics

Therapeutic silencing of mTOR by systemically administered siRNA-loaded neutral liposomal nanoparticles inhibits DMBA-induced mammary carcinogenesis

Abstract

Background

Mammary carcinogenesis possesses great challenges due to the lack of effectiveness of the multiple therapeutic options available. Gene therapy-based cancer treatment strategy provides more targeting accuracy, fewer side effects, and higher therapeutic efficiency. Downregulation of the oncogene mTOR by mTOR-siRNA is an encouraging approach to reduce cancer progression. However, its employment as means of therapeutic strategy has been restricted due to the unavailability of a suitable delivery system.

Methods

A suitable nanocarrier system made up of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) has been developed to prevent degradation and for proficient delivery of siRNA. This was followed by in vitro and in vivo anti-breast cancer efficiency analysis of the mTOR siRNA-loaded neutral liposomal formulation (NL-mTOR-siRNA).

Results

In our experiment, a profound reduction in MCF-7 cell growth, proliferation and invasion was ascertained following extensive downregulation of mTOR expression. NL-mTOR-siRNA suppressed tumour growth and restored morphological alterations of DMBA-induced breast cancer. In addition, neutral liposome enhanced accumulation of siRNA in mammary cancer tissues facilitating its deep cytosolic distribution within the tumour, which allows apoptosis thereby facilitating its anti-tumour potential.

Conclusion

Hence, the current study highlighted the augmented ground for therapies aiming toward cancerous cells to diminish mTOR expression by RNAi in managing mammary carcinoma.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Morphological characterisation of DOPC-based neutral nanoliposome.
Fig. 2: Haemolysis assay and cellular uptake analysis of neutral nanoliposome.
Fig. 3: In vitro activity of mTOR siRNA-loaded neutral liposome.
Fig. 4: In vivo uptake of siRNA-loaded neutral liposome into the tumour tissue.
Fig. 5: In vivo anti-tumour efficacy of mTOR siRNA-loaded neutral liposome in DMBA-induced breast tumour model in SD rats.
Fig. 6: In vivo mTOR downregulation following NL-mTOR-siRNA administration.
Fig. 7: Induction of apoptosis in DMBA-induced mammary tumours by mTOR siRNA-loaded neutral liposome.
Fig. 8: Histopathological analysis of rats treated with or without mTOR siRNA-loaded neutral liposome.

Similar content being viewed by others

References

  1. Zhou B, Li M, Xu X, Yang L, Ye M, Chen Y, et al. Integrin α2β1 targeting DGEA-modified liposomal doxorubicin enhances antitumor efficacy against breast cancer. Mol Pharm. 2021;18:2634–46.

    Article  CAS  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  PubMed  Google Scholar 

  3. Mathur P, Sathishkumar K, Chaturvedi M, Das P, Sudarshan KL, Santhappan S, et al. Cancer statistics, 2020: report from National Cancer Registry Programme, India. JCO Glob Oncol. 2020;6:1063–75.

    Article  PubMed  Google Scholar 

  4. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet. 1998;352:930–42.

    Article  Google Scholar 

  5. Gentzler RD, Altman JK, Platanias LC. An overview of the mTOR pathway as a target in cancer therapy. Expert Opin Ther Targets. 2012;16:481–9.

    Article  CAS  PubMed  Google Scholar 

  6. Sahu R, Pattanayak SP. Strategic developments & future perspective on gene therapy for breast cancer: role of mTOR and Brk/PTK6 as molecular targets. Curr Gene Ther. 2020;20:237–58.

    Article  CAS  PubMed  Google Scholar 

  7. Zou Z, Tao T, Li H, Zhu X. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell Biosci. 2020;10:1–1.

    Article  CAS  Google Scholar 

  8. Tapia O, Riquelme I, Leal P, Sandoval A, Aedo S, Weber H, et al. The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch. 2014;465:25–33.

    Article  CAS  PubMed  Google Scholar 

  9. Singh BN, Kumar D, Shankar S, Srivastava RK. Rottlerin induces autophagy which leads to apoptotic cell death through inhibition of PI3K/Akt/mTOR pathway in human pancreatic cancer stem cells. Biochem Pharm. 2012;84:1154–63.

    Article  CAS  PubMed  Google Scholar 

  10. Liu J, Li HQ, Zhou FX, Yu JW, Sun L, Han ZH. Targeting the mTOR pathway in breast cancer. Tumor Biol. 2017;39:1010428317710825.

    Article  Google Scholar 

  11. Guerrero-Zotano A, Mayer IA, Arteaga CL. PI3K/AKT/mTOR: role in breast cancer progression, drug resistance, and treatment. Cancer Metastasis Rev. 2016;35:515–24.

    Article  CAS  PubMed  Google Scholar 

  12. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411:494–8.

    Article  CAS  PubMed  Google Scholar 

  13. Kapoor M, Burgess DJ, Patil SD. Physicochemical characterization techniques for lipid based delivery systems for siRNA. Int J Pharm. 2012;427:35–57.

    Article  CAS  PubMed  Google Scholar 

  14. Shen J, Zhang W, Qi R, Mao ZW, Shen H. Engineering functional inorganic–organic hybrid systems: advances in siRNA therapeutics. Chem Soc Rev. 2018;47:1969–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pecot CV, Calin GA, Coleman RL, Lopez-Berestein G, Sood AK. RNA interference in the clinic: challenges and future directions. Nat Rev Cancer. 2011;11:59–67.

    Article  CAS  PubMed  Google Scholar 

  16. Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov. 2010;9:615–27.

    Article  CAS  PubMed  Google Scholar 

  17. Chakrabarti S, Finnes HD, Mahipal A. Fibroblast growth factor receptor (FGFR) inhibitors in cholangiocarcinoma: current status, insight on resistance mechanisms and toxicity management. Expert Opin Drug Metab Toxicol. 2022;14:1–4.

    Google Scholar 

  18. Rossi JJ, Rossi DJ. siRNA drugs: here to stay. Mol Ther. 2021;29:431–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov. 2009;8:129–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Merritt WM, Bar-Eli M, Sood AK. The dicey role of Dicer: implications for RNAi therapy. Cancer Res. 2010;70:2571–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tanaka T, Mangala LS, Vivas-Mejia PE, Nieves-Alicea R, Mann AP, Mora E, et al. Sustained small interfering RNA delivery by mesoporous silicon particles. Cancer Res. 2010;70:3687–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Di Paolo D, Brignole C, Pastorino F, Carosio R, Zorzoli A, Rossi M, et al. Neuroblastoma-targeted nanoparticles entrapping siRNA specifically knockdown ALK. Mol Ther. 2011;19:1131–40.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Liyanage PY, Hettiarachchi SD, Zhou Y, Ouhtit A, Seven ES, Oztan CY, et al. Nanoparticle-mediated targeted drug delivery for breast cancer treatment. Biochim Biophys Acta Rev Cancer. 2019;1871:419–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Filion MC, Phillips NC. Major limitations in the use of cationic liposomes for DNA delivery. Int J Pharm. 1998;162:159–70.

    Article  CAS  Google Scholar 

  25. Foged C, Nielsen HM, Frokjaer S. Liposomes for phospholipase A2 triggered siRNA release: preparation and in vitro test. Int J Pharm. 2007;331:160–6.

    Article  CAS  PubMed  Google Scholar 

  26. Halder J, Kamat AA, Landen CN, Han LY, Lutgendorf SK, Lin YG, et al. Focal adhesion kinase targeting using in vivo short interfering RNA delivery in neutral liposomes for ovarian carcinoma therapy. Clin Cancer Res. 2006;12:4916–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Landen CN, Chavez-Reyes A, Bucana C, Schmandt R, Deavers MT, Lopez-Berestein G, et al. Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. Cancer Res. 2005;65:6910–8.

    Article  CAS  PubMed  Google Scholar 

  28. Song Y, Zhou B, Du X, Wang Y, Zhang J, Ai Y, et al. Folic acid (FA)-conjugated mesoporous silica nanoparticles combined with MRP-1 siRNA improves the suppressive effects of myricetin on non-small cell lung cancer (NSCLC). Biomed Pharmacother. 2020;125:109561.

    Article  CAS  PubMed  Google Scholar 

  29. Alinejad V, Somi MH, Baradaran B, Akbarzadeh P, Atyabi F, Kazerooni H, et al. Co-delivery of IL17RB siRNA and doxorubicin by chitosan-based nanoparticles for enhanced anticancer efficacy in breast cancer cells. Biomed Pharmacother. 2016;83:229–40.

    Article  CAS  PubMed  Google Scholar 

  30. Kumar K, Maiti B, Kondaiah P, Bhattacharya S. Efficacious gene silencing in serum and significant apoptotic activity induction by survivin downregulation mediated by new cationic gemini tocopheryl lipids. Mol Pharm. 2015;12:351–61.

    Article  CAS  PubMed  Google Scholar 

  31. Bose P, Priyam A, Kar R, Pattanayak SP. Quercetin loaded folate targeted plasmonic silver nanoparticles for light activated chemo-photothermal therapy of DMBA induced breast cancer in Sprague Dawley rats. RSC Adv. 2020;10:31961–78(a).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tekedereli I, Alpay SN, Akar U, Yuca E, Ayugo-Rodriguez C, Han HD, et al. Therapeutic silencing of Bcl-2 by systemically administered siRNA nanotherapeutics inhibits tumor growth by autophagy and apoptosis and enhances the efficacy of chemotherapy in orthotopic xenograft models of ER (−) and ER (+) breast cancer. Mol Ther Nucleic Acids. 2013;2:e121.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Jin Y, Liang X, An Y, Dai Z. Microwave-triggered smart drug release from liposomes co-encapsulating doxorubicin and salt for local combined hyperthermia and chemotherapy of cancer. Bioconjug Chem. 2016;27:2931–42.

    Article  CAS  PubMed  Google Scholar 

  34. Tekedereli I, Alpay SN, Tavares CD, Cobanoglu ZE, Kaoud TS, Sahin I, et al. Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer. PLoS ONE. 2012;7:e41171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li Y, Cheng Q, Jiang Q, Huang Y, Liu H, Zhao Y, et al. Enhanced endosomal/lysosomal escape by distearoyl phosphoethanolamine-polycarboxybetaine lipid for systemic delivery of siRNA. J Control Release. 2014;176:104–14.

    Article  CAS  PubMed  Google Scholar 

  36. Acharya R, Chacko S, Bose P, Lapenna A, Pattanayak SP. Structure based multitargeted molecular docking analysis of selected furanocoumarins against breast cancer. Sci Rep. 2019;9:1–3.

    Article  Google Scholar 

  37. Haque MW, Bose P, Siddique MU, Sunita P, Lapenna A, Pattanayak SP. Taxifolin binds with LXR (α & β) to attenuate DMBA-induced mammary carcinogenesis through mTOR/Maf-1/PTEN pathway. Biomed Pharmacother. 2018;105:27–36.

    Article  CAS  PubMed  Google Scholar 

  38. Kumar A, Sunita P, Jha S, Pattanayak SP. Daphnetin inhibits TNF‐α and VEGF‐induced angiogenesis through inhibition of the IKK s/IκBα/NF‐κB, Src/FAK/ERK 1/2 and Akt signalling pathways. Clin Exp Pharm Physiol. 2016;43:939–50.

    Article  CAS  Google Scholar 

  39. Xiao W, Zhang W, Huang H, Xie Y, Zhang Y, Guo X, et al. Cancer targeted gene therapy for inhibition of melanoma lung metastasis with eiF3i shRNA loaded liposomes. Mol Pharm. 2019;17:229–38.

    Article  PubMed  Google Scholar 

  40. Bertrand JR, Pottier M, Vekris A, Opolon P, Maksimenko A, Malvy C. Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo. Biochem Biophys Res Commun. 2002;296:1000–4.

    Article  CAS  PubMed  Google Scholar 

  41. Sahu R, Kar RK, Sunita P, Bose P, Kumari P, Bharti S, et al. LC-MS characterized methanolic extract of Zanthoxylum armatum possess anti-breast cancer activity through nrf2-keap1 pathway: an in-silico, in-vitro and in-vivo evaluation. J Ethnopharmacol. 2021;269:113758.

    Article  CAS  PubMed  Google Scholar 

  42. Kumar A, Sunita P, Jha S, Pattanayak SP. 7, 8-Dihydroxycoumarin exerts antitumor potential on DMBA-induced mammary carcinogenesis by inhibiting ERα, PR, EGFR, and IGF1R: involvement of MAPK1/2-JNK1/2-Akt pathway. J Physiol Biochem. 2018;74:223–34.

    Article  CAS  PubMed  Google Scholar 

  43. Chen Y, Zhu X, Zhang X, Liu B, Huang L. Nanoparticles modified with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy. Mol Ther. 2010;18:1650–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Clogston JD, Patri AK. Zeta potential measurement. Methods Mol Biol. 2011;697:63–70.

    Article  CAS  PubMed  Google Scholar 

  45. Plumb JA. Cell sensitivity assays: clonogenic assay. In: Langdon SP, editor. Cancer cell culture, methods in molecular medicine. Totowa, NJ: Humana Press Inc.; 2004. pp. 159–64.

  46. Teymouri M, Badiee A, Golmohammadzadeh S, Sadri K, Akhtari J, Mellat M, et al. Tat peptide and hexadecylphosphocholine introduction into pegylated liposomal doxorubicin: an in vitro and in vivo study on drug cellular delivery, release, biodistribution and antitumor activity. Int J Pharm. 2016;511:236–44.

    Article  CAS  PubMed  Google Scholar 

  47. Barenholz YC. Doxil®—the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160:117–34.

    Article  CAS  PubMed  Google Scholar 

  48. Walkey CD, Olsen JB, Guo H, Emili A, Chan WC. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J Am Chem Soc. 2012;134:2139–47.

    Article  CAS  PubMed  Google Scholar 

  49. Argilés JM, Azcón-Bieto J. The metabolic environment of cancer. Mol Cell Biochem. 1988;81:3–17.

    Article  PubMed  Google Scholar 

  50. Pattanayak SP, Mazumder PM. Therapeutic potential of Dendrophthoe falcata (Lf) Ettingsh on 7, 12-dimethylbenz (a) anthracene-induced mammary tumorigenesis in female rats: effect on antioxidant system, lipid peroxidation, and hepatic marker enzymes. Comp Clin Pathol. 2011;20:381–92.

    Article  Google Scholar 

  51. Song F, Sakurai N, Okamoto A, Koide H, Oku N, Dewa T, et al. Design of a novel PEGylated liposomal vector for systemic delivery of siRNA to solid tumors. Biol Pharm Bull. 2019;42:996–1003.

    Article  CAS  PubMed  Google Scholar 

  52. Badran M, Shalaby K, Al-Omrani A. Influence of the flexible liposomes on the skin deposition of a hydrophilic model drug, carboxyfluorescein: dependency on their composition. Sci World J 2012;2012:134876.

    Article  Google Scholar 

  53. Yang C, Attia AB, Tan JP, Ke X, Gao S, Hedrick JL, et al. The role of non-covalent interactions in anticancer drug loading and kinetic stability of polymeric micelles. Biomaterials. 2012;33:2971–9.

    Article  CAS  PubMed  Google Scholar 

  54. Desai MP, Labhasetwar V, Amidon GL, Levy RJ. Gastrointestinal uptake of biodegradable microparticles: effect of particle size. Pharm Res. 1996;13:1838–45.

    Article  CAS  PubMed  Google Scholar 

  55. Prakash S, Malhotra M, Shao W, Tomaro-Duchesneau C, Abbasi S. Polymeric nanohybrids and functionalized carbon nanotubes as drug delivery carriers for cancer therapy. Adv Drug Deliv Rev. 2011;63:1340–51.

    Article  CAS  PubMed  Google Scholar 

  56. Haley B, Frenkel E. Nanoparticles for drug delivery in cancer treatment. Urol Oncol. 2008;26:57–64.

    Article  CAS  PubMed  Google Scholar 

  57. Arranja AG, Pathak V, Lammers T, Shi Y. Tumor-targeted nanomedicines for cancer theranostics. Pharm Res. 2017;115:87–95.

    Article  CAS  Google Scholar 

  58. Miller CR, Bondurant B, McLean SD, McGovern KA, O’Brien DF. Liposome− cell interactions in vitro: effect of liposome surface charge on the binding and endocytosis of conventional and sterically stabilized liposomes. Biochemistry 1998;37:12875–83.

    Article  CAS  PubMed  Google Scholar 

  59. Lieleg O, Baumgärtel RM, Bausch AR. Selective filtering of particles by the extracellular matrix: an electrostatic bandpass. Biophys J. 2009;97:1569–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nomura T, Koreeda N, Yamashita F, Takakura Y, Hashida M. Effect of particle size and charge on the disposition of lipid carriers after intratumoral injection into tissue-isolated tumors. Pharm Res. 1998;15:128–32.

    Article  CAS  PubMed  Google Scholar 

  61. Xia Y, Tian J, Chen X. Effect of surface properties on liposomal siRNA delivery. Biomaterials 2016;79:56–68.

    Article  CAS  PubMed  Google Scholar 

  62. Easton JB, Houghton PJ. mTOR and cancer therapy. Oncogene. 2006;25:6436–46.

    Article  CAS  PubMed  Google Scholar 

  63. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–45.

    Article  CAS  PubMed  Google Scholar 

  64. Vara JÁ, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30:193–204.

    Article  CAS  Google Scholar 

  65. Butt G, Shahwar D, Qureshi MZ, Attar R, Akram M, Birinci Y, et al. Role of mTORC1 and mTORC2 in breast cancer: therapeutic targeting of mTOR and its partners to overcome metastasis and drug resistance. Adv Exp Med Biol. 2019;1152:283–92.

  66. Ma BL, Shan MH, Sun G, Ren GH, Dong C, Yao X, et al. Immunohistochemical analysis of phosphorylated mammalian target of rapamycin and its downstream signaling components in invasive breast cancer. Mol Med Rep. 2015;12:5246–54.

    Article  CAS  PubMed  Google Scholar 

  67. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012;485:55–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Steeg PS. Targeting metastasis. Nat Rev Cancer. 2016;16:201–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Berven LA, Willard FS, Crouch MF. Role of the p70S6K pathway in regulating the actin cytoskeleton and cell migration. Exp Cell Res. 2004;296:183–95.

    Article  CAS  PubMed  Google Scholar 

  70. Chen JS, Wang Q, Fu XH, Huang XH, Chen XL, Cao LQ, et al. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP‐9. Hepatol Res. 2009;39:177–86.

    Article  CAS  PubMed  Google Scholar 

  71. Liu L, Li F, Cardelli JA, Martin KA, Blenis J, Huang S. Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene 2006;25:7029–40.

    Article  CAS  PubMed  Google Scholar 

  72. Langer EM, Kendsersky ND, Daniel CJ, Kuziel GM, Pelz C, Murphy KM, et al. ZEB1-repressed microRNAs inhibit autocrine signaling that promotes vascular mimicry of breast cancer cells. Oncogene 2018;37:1005–19.

    Article  CAS  PubMed  Google Scholar 

  73. Verrax J, Defresne F, Lair F, Vandermeulen G, Rath G, Dessy C, et al. Delivery of soluble VEGF receptor 1 (sFlt1) by gene electrotransfer as a new antiangiogenic cancer therapy. Mol Pharm. 2011;8:701–8.

    Article  CAS  PubMed  Google Scholar 

  74. Mollard S, Mousseau Y, Baaj Y, Richard L, Cook-Moreau J, Monteil J, et al. How can grafted breast cancer models be optimized? Cancer Biol Ther. 2011;12:855–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Haque MW, Pattanayak SP. Taxifolin inhibits 7, 12-dimethylbenz (a) anthracene-induced breast carcinogenesis by regulating AhR/CYP1A1 signaling pathway. Pharmacogn Mag. 2017;13:S749–55.

    Google Scholar 

  76. Bose P, Pattanayak SP, Priyam A. Herniarin, a natural coumarin loaded novel targeted plasmonic silver nanoparticles for light activated chemo-photothermal therapy in preclinical model of breast cancer. Pharmacogn Mag. 2020;16:474–85 (b).

    Article  Google Scholar 

  77. Zhang HW, Hu JJ, Fu RQ, Liu X, Zhang YH, Li J, et al. Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells. Sci Rep. 2018;8:1–3.

    Google Scholar 

  78. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics. Br J cancer. 1972;26:239–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Spagnou S, Miller AD, Keller M. Lipidic carriers of siRNA: differences in the formulation, cellular uptake, and delivery with plasmid DNA. Biochemistry. 2004;43:13348–56.

    Article  CAS  PubMed  Google Scholar 

  80. Wagner MJ, Mitra R, McArthur MJ, Baze W, Barnhart K, Wu SY, et al. Preclinical mammalian safety studies of EPHARNA (DOPC nanoliposomal EphA2-targeted siRNA). Mol Cancer Ther. 2017;16:1114–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Sonoke S, Ueda T, Fujiwara K, Sato Y, Takagaki K, Hirabayashi K, et al. Tumor regression in mice by delivery of Bcl-2 small interfering RNA with pegylated cationic liposomes. Cancer Res. 2008;68:8843–51.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the support provided by the Central Instrumentation facility (CIF), Birla Institute of Technology, Mesra, Ranchi and HR-TEM facility of Vellore Institute of Technology in the characterisation of liposomal preparation.

Funding

This study was supported by Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India. This work has been funded by UGC (201819-NFO-2018-19-OBC-ORI-80495).

Author information

Authors and Affiliations

Authors

Contributions

RS and SPP conducted the experiments and wrote the manuscript with equal contribution. SPP and RS was responsible for confocal microscopy, Western blot, immunohistochemistry and flow cytometry. RS and SJ took part in the in vivo experiments. SJ analysed the data and revised the manuscript. SPP designed the research plan, analysed the data and revised the manuscript. All authors have approved the manuscript.

Corresponding author

Correspondence to Shakti Prasad Pattanayak.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This animal study was approved by the Institutional Animal Ethical Committee, Birla Institute of Technology, Mesra, Ranchi (approval no. 1972/PH/BIT/113/20/IAEC). All animal experiments were conducted in accordance with the Institutional Animal Ethical Committee (IAEC) regulation. This study did not include patient participation or analysis of patient data.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sahu, R., Jha, S. & Pattanayak, S.P. Therapeutic silencing of mTOR by systemically administered siRNA-loaded neutral liposomal nanoparticles inhibits DMBA-induced mammary carcinogenesis. Br J Cancer 127, 2207–2219 (2022). https://doi.org/10.1038/s41416-022-02011-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-022-02011-1

Search

Quick links